Protective immunity against chronic infectious diseases such as TB will almost certainly require the generation of potent cellular immunity. To that end, we have recently developed a proprietary form of immunization (combined TLR/CD40-agonist immunization) which elicits a T cell response exponentially greater than traditional vaccination methods, and produces potent protective T cell immune memory. The overall goal of these experiments is to develop a novel and potent vaccine platform for chronic infectious diseases, with a production cost and shelf life consistent with the needs of the third world. We therefore propose to produce and evaluate the generation and maintenance of protective cellular immunity following immunization with both protein-based and DNA-based combined TLR/CD40-agonist vaccine. Importantly we will evaluate these vaccines for their induction of protective immunity against aerosol challenge with TB. While CD40 agonists and TLR agonists have been used separately in previous clinical settings, combining these agonists into a proprietary vaccine formulation is a novel, patented concept with no previous clinical exposure. Thus, the studies proposed below constitute an innovative vaccine platform with the potential for high impact as a prophylactic and/or therapeutic TB vaccine. PUBLIC HEALTH RELEVANCE: Project Narrative ImmuRx has developed a novel, patented vaccine platform capable of generating immunity 10 times greater than conventional vaccination methods. Preliminary data has shown this vaccine to be successful in protecting against both viral and bacterial infections and we will now examine how well the vaccine can protect against infection with TB, a representative of a globally significant chronic infectious disease. The results of these studies will lead to pre-IND studies in anticipation of clinical trials and subsequent commercialization to bring this powerful treatment to patients in need.